NO882887L - SELECTED N6-SUBSTITUTED ADENOSINES WITH SELECTIVE A2 BINDING ACTIVITY. - Google Patents

Description

The compounds according to the present invention

is related to the N<6-> substituted adenosines of pending US Patent Application No. 756,922, dated June 17, 1985, which is a "continuation" of US Patent Application No. 621,943, dated June 22, 1984, now issued, which is a "continuation in part" of now issued US Patent Application No. 519,284, dated August 1, 1983.

The compounds produced according to the invention have

a surprisingly greater affinity for A2 receptors than for A^ receptors. The compounds have very valuable central nervous system and cardiovascular properties, such as analgesic, antipsychotic, sedative, antihypertensive and cardiotonic activity, especially antianginal and vasodilatory effects.

The above-mentioned pending application and the references indicated there thus provide a background for the present invention, including descriptions of literature trials, where the compounds according to the present invention have been shown to have the activity described here. Pending US patent application No. 756,922 is therefore hereby included as part of the present application.

References regarding the hitherto unknown method according to the present invention include European patent application no. 222330A, J. Med. Chem., vol. 29, No. 9, pp. 1683-89 (1986) or WO8600310 and J. Med. Chem., vol. 23, pp. 313-9

(1986) or US Patent No. 3,852,268. None of these references mention the preparation of a 5'-uronamide from inosine-isopropylidene according to the present method, with unexpected advantages.

The present invention relates to a compound of formula

IN

or a pharmaceutically acceptable acid addition salt thereof, wherein Ar is or

where XlfX2, X3, YlfY2 and Y3 may be independently selected from hydrogen, halogen, lower alkyl, lower alkylthio or alkoxy, and where XlfX2 or X3 may further be trifluoromethyl, provided that Y2 or Y3 must be hydrogen, except when Y: is hydrogen and Y2 and Y3 together is -(CH)4-, below it

further general assumption that at least two of XlfX2, X3/YltY2 and Y3 are not hydrogen.

R2' and R3' are each independently hydrogen, alkanoyl with 2-12 carbon atoms in a straight or branched alkyl chain, which may be substituted with amino, benzoyl or benzoyl which is substituted with lower alkyl, lower alkoxy, halogen or trifluoromethyl, where R2' and R3' can further be linked together to form either a 5-membered alkylidene ring with up to a total of 20 carbon atoms, which e.g. isopropylidene, or a cyclic phosphate diester, and R5<1> can be phosphate, hydrogen or dihydrogen phosphate, or an alkali metal or ammonium or dialkali or diammonium salt thereof, such as e.g. P03Na2,

Z is -(CH2)-Q, where Q is selected from hydrogen, hydroxy, halogen, cyano, azido, amino, lower alkoxy, lower acyloxy, lower thioalkyl, lower sulfonylalkyl,

where L is 0-4, and

R 6 is hydrogen or R 6 may further, when L is 0, be a side chain of a naturally occurring amino acid, such as benzyl, as found in a phenylalanine ester, or isopropyl, as found in an ethyl ester, or

where k is 0-4,

-P(=Y)(OR")2, -P(=Y)(OR")(OR'") , and together with R<3> form

where Y is oxygen or sulfur and R" and R'" independently are hydrogen or lower alkyl, or (2)

where J is 0, S, NR7, where R7 is hydrogen, lower alkyl or cycloalkyl with from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and the like, or 1- or 2-methylcyclopropyl, 1- or 2-ethylcyclobutyl and the like, and

T is (a) NR4R5, where R4 is straight-chain lower alkyl of 1-4 carbon atoms, hydroxy-, lower alkoxy- or halogen-substituted straight-chain lower alkyl of 1-4 carbon atoms, cyclopropyl, secondary alkyl of 3-6 carbon atoms, hydroxy-, lower alkoxy -or halogen-substituted secondary alkyl with 3-6 carbon atoms, alkenyl with 3-6 carbon atoms, aralkyl with 1-4 carbon atoms in the alkyl chain and optionally substituted in the aryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups, and hetero-arylalkyl with 1- 4 carbon atoms in the alkyl chain, and optionally substituted in the heteroaryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups, and

R5 is hydrogen or straight-chain lower alkyl with 1-4 carbon atoms, or

(b) 0R4, where R4 has the above meaning.

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above-mentioned formula I, with a pharmaceutically acceptable carrier, as well as a method for the treatment of mammals by administering to such mammals a dosage form of a compound of the formula I as defined above .

Finally, the present invention relates to a so far

unknown process for the preparation of a compound of formula

which includes treating a compound with a formula

with H2Cr04in acetone.

In the compounds of formula I, the term "lower alkyl" shall include a straight-chain or branched alkyl group of 1-6 carbon atoms, such as e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, amyl, isoamyl, neopentyl, hexyl, and the like.

Halogen includes in particular chlorine or bromine.

Lower Alkoxy and ThioAlkoxy are O-alkyl or S-alkyl having from 1 to 6 carbon atoms as defined above for "lower alkyl".

The compounds of formula I are useful both in the free base form and in the form of acid addition salts. Both forms fall within the scope of the invention. In practice, use of the salt form corresponds to use of the base form. Suitable pharmaceutically acceptable salts, which fall within the scope of the invention, are those derived from mineral acids, such as hydrochloric acid and sulfuric acid, as well as organic acids, such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., which respectively give the hydrochloride, sulfate, ethanesulfonate, benzenesulfonate , p-toluenesulfonate, etc. (see, e.g., "Pharmaceutical Salts", J. Pharm. Sci., (1977) 66(1):1-19).

The acid addition salts of the basic compounds are prepared either by dissolving the free base form in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid, or isolating the salt by evaporation of the solution, or by reacting the free base and acid in an organic solvent, whereby the salt is precipitated directly or can be obtained by concentrating the solution.

Preferred compounds of formula I are

where Xx and X3 have the meanings given above and Y is Y1# when Yx is not hydrogen.

Another group of preferred compounds of formula I are

where XltX2 and Y have the meanings given above.

The most preferred compound according to the present invention has the formula II7 wherein X1 and X3 are methoxy and Y is methyl.

The present invention also relates to hitherto unknown methods for the preparation of a compound of formula I as follows: In general, the compounds of formula I can be synthesized by converting an aryl aldehyde of formula (V) where Xl7X2 and X3 have the meanings indicated above, to the corresponding w- nitrostyrene of formula (IV) where XlfX2 and X3 have the meanings given above. The conversion takes place by (1) treatment with nitromethane in a basic medium, i.e. in a solvent such as methanol, ethanol or aqueous methenyl in the presence of NaOH, and (2) chlorosulfonylmethane in the presence of approx. two equivalents of triethylamine in an aprotic solvent such as dichloromethane. The w-nitrostyrene of formula IV is then treated with an organometallic compound of formula IVa where Yi f Y2 and Y3 have the meanings given above and M is a moiety, preferably such that IVa is a Grignard or lithium derivative in an aprotic solvent system (preferably toluene ether) at a low temperature (preferably from -10° to -40°C) using reaction conditions known to those skilled in the art in connection with the Grignard or lithium derivative. The treatment with the organometallic compound gives a compound of formula (III) where X1#X2, X3, Yx, Y2 and Y3 have the meanings indicated above. The compound of formula III is then reduced by treatment with e.g. lithium aluminum hydride using conditions skilled in the art, to form a compound of formula (II)

where X1; X2, X3, Ylr Y2 and Y3 have the meanings given above.

Finally, the compound of formula II is coupled with 6-chloropurine riboside in the presence of triethylamine, according to the method described in US patent 756,922, to obtain a compound of formula I as defined above.

The procedure described above is as follows:

Although the N<6-> side chain is prepared as described above, a particularly preferred, hitherto unknown, method for preparing the uronamide part of the molecule for compound I is also according to the present invention. It is as follows:

The previously unknown process shown above for the preparation of the uronamide moieties on the compound of formula I is generally carried out by treating the compound of formula X with ethyl orthoformate and tosic acid in acetone to form the isopropylidene XI in 80-90% yield. Oxidation of XI with chromic acid in acetone gives the uronic acid XII in 53-60% yield. This can be converted to acid XIII in 80% yield by treatment with a suitable 2,2-diarylethylamine and triethylamine in ethanol, and then amidated with a suitable primary amine and a condensing agent, such as dicyclohexylcarbodiimide/l-hydroxybenzotriazole or N-methyl-2 -fluoropyridinium tosylate/triethylamine to form the protected nucleoside XIV, which upon acid hydrolysis, preferably with aqueous TFA at 0°C, yields the desired nucleoside XV. Alternatively, compound XIV can be formed from uronic acid XII by amidation of the uronic acid moiety as described to form XIV, followed by replacement of C6-C1 under the same conditions as previously described.

Although this procedure is related to the previous one

in international application 8600310 described, which follows the procedure according to J. Med. Chem., vol. 23, pp. 313-9 (1986), it has several clear advantages. In the present method, the isopropylidation of inosine is physically prevented, while, on the other hand, the conversion from X to XI is very simple in terms of execution.

Furthermore, the oxidation of the inosine-isopropylidene to the corresponding uronic acid according to the previously known methods is also cumbersome and the present inventors never succeeded in reaching the stated yields (=65%), but consistently lower yields (20-25%) ). The conversion of XI to XII proved to be reproducible in 50-60% yield, and the entire reaction can be carried out in 2-4 hours, providing a significant time saving. Several attempts to convert inosine-isopropylidene-5<1->uronic acid to intermediate XIV under the previously stated conditions fail, while, on the other hand, the methods presented here reproducibly allowed XV (or XIV) to be prepared from the corresponding uronic acids in 60-95% yield. Therefore, the present method unexpectedly provides an overall, execution-wise much simpler method than previously stated methods, and the total process X to XV can thus be carried out on a laboratory scale in 20-30% total yield within 3 working days.

The starting materials for the above-described methods for preparing the compounds of formula I are generally known, commercially available or can be prepared by methods that are either known or analogous to known.

Variations in the methods according to the present invention fall within the general knowledge of the person skilled in the art. The products from the methods are isolated using conventional means, such as extraction, distillation, chromatography, etc.

The compounds of formula I have now been shown to have a surprising and unexpected preference for binding to A2-adenosine receptors.

By molecular modelling, the compounds according to the present invention can be said to preferentially bind to A2 receptors. Such an A2 bond indicates a mechanism of action different from that previously indicated for known adenosine derivatives for general applications. Such applications are, in view of the new A2 binding preference, unexpected compared to the different affinities for the Ax and A2 receptors as indicated in the above-mentioned US patent application 756,922. The compounds according to the present invention therefore represent a new mechanism of action which cannot be predicted from previously presented data. Furthermore, the demonstrated difference between A2 and A1 receptor binding is in the range from 1.5 to 35 times. Furthermore, activity in the animal experiments for the mentioned compounds exceeds that which could be expected on the basis of the measured Ai receptor binding of these compounds, and it is therefore also surprising. Among the compounds in question, the effect of the compound according to Example 19 in the MAST test is also not reversed by an A selective antagonist, in contrast to selected compounds from the examples in the above-mentioned US patent application 756,922. Furthermore, it has now been shown that the compound according to Example 19 has a different effect on dopamine receptors than selected compounds from the examples, again according to the above-mentioned US patent application 756,922.

These compounds of formula I are active in animal experiments that can predict neuroleptic activity, for the treatment of severe psychoses such as schizophrenia. The compounds according to the invention also have sedative/hypnotic properties and as such are useful for the treatment of pain.

Furthermore, the compounds according to the present invention are useful for the treatment of congestive heart failure. In particular, it has been shown that the compounds of formula I have vasodilatory properties with a marked selectivity for coronary rather than peripheral vasculature and a positive inotropic effect, which increases blood flow and is valuable in the treatment of angina and congestive heart failure. For a similar effect with an adenosine, reference is made to patent application PD-3545.

The biological data from experiments corresponding to those described in US patent application 756,922 for the compounds according to the present invention are summarized in the following tables for the indicated examples described hereafter.

The present invention therefore also includes a pharmaceutical composition for the treatment of psychoses, sleep disorders, pain or cardiovascular diseases comprising a corresponding antipsychotic, sedative, analgesic or cardiovascular disease-effective amount of a compound of formula I as defined above, with a pharmaceutically acceptable carrier.

Treatment of cardiovascular diseases means applicability as antihypertensive agents for the treatment of high blood pressure. Furthermore, the treatment increases coronary blood flow, e.g. as a vasodilator, and is therefore also useful for the treatment of angina and congestive heart failure.

The present invention therefore further comprises a method for the treatment of psychoses, sleep disorders, pain or cardiovascular diseases in mammals which have such disorders, and which comprises administering to such mammals either orally or parenterally a corresponding pharmaceutical composition with a compound of formula I as defined above , in suitable dosage form.

The compositions and methods of administration must be understood in accordance with the state of the art, e.g. as described in US Patent Application 756,922.

The amount of active compound in a unit dose of a preparation can be varied or adjusted from 1 mg to 500 mg, preferably 5-100 mg according to the particular application and the strength of the active ingredient. If desired, the compositions may also contain other compatible therapeutic agents.

For a therapeutic application as described above, the dose range for a 70 kg mammal is from 0.01 to 100 mg/kg body weight per day or preferably 0.1 to 50 mg/kg body weight per day. However, the dosages can be varied depending on the patient's requirements, the severity of the condition and the compound used. Determining the correct dose for a specific situation is a professional matter. Generally, treatment is initiated with smaller doses, which are less than the optimal dose of the compound. The dosage is then increased in small increments until the optimal effect under the circumstances is achieved. For convenience, the total daily dose can be divided and administered in portions during the day if desired.

The invention is further illustrated in the following examples.

Example 1

N, 6-(2, 6- dimethylphenyl)- 2- phenylethyl) adenosine

a) E,2-(2,6-dimethylphenyl)nitroethene

Aqueous sodium hydroxide (2.5M, 20 ml) was added during 15

minutes added dropwise to a solution of 2,6-dimethylbenzaldehyde (6.7 g, 50 mmol) and nitromethane (3.1 g, 50 rnmol) in methanol (25 mL) stirred under N 2 at 0°C. After an additional 15 minutes, the reaction mixture was cooled by pouring onto dilute hydrochloric acid (0.5M, 100 mL) and extracted with ether (3 x 25 mL). The combined extracts were washed with water (2 x 25 ml)

and saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the remaining yellow oil dissolved in CH 2 Cl 2 (150 mL) stirred under N 2 at 0°C. Mesyl chloride (5.7 g, 50 mmol) in CH 2 Cl 2 (25 mL) and then triethylamine (10.1 g, 100 mmol) in CH 2 Cl 2 (25 mL) were successively added to the solution. After 1.5 hours, the reaction mixture was poured into dilute hydrochloric acid (0.5M, 200 ml). The layers were separated and the aqueous layer extracted with CH 2 Cl 2 (50 mL). The combined organic phases were washed with water (2 x 50 ml), saturated saline (50 ml)

and dried (MgSO 4 ). The solvent was removed under reduced pressure to leave the nitrostyrene (8.33 g, 96%) as a light brown oil.

NMR (CDCl 3 ) δ 8.22 (1H, d, J=14Hz); 6.9-7.4 (4H, m); 2.41 (6H, p).

b) 2-(2,6-dimethylphenyl)-2-phenylethylamine

Phenylmagnesium bromide (2.9M in ether, 5 mL, 14.5 mmol) was added

over 10 minutes was added dropwise to a solution of E,2-(2,6-dimethylphenyl)nitroethene (1.77 g, 10 mmol) in toluene (50 mL) stirred under N2 at -30°C. The solution turned red, and after an additional 15 minutes at -30°C, the reaction mixture was cooled by the addition of dilute hydrochloric acid (0.4M, 50 mL). The layers were separated and the aqueous layer extracted with toluene

(25ml). The combined organic phases were washed with water (25 mL, emulsions common at this stage), saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure to leave crude diarylnitroethane (2.05 g) as a yellow oil. This was dissolved in ether (25 ml) and added dropwise over 20 minutes to a suspension of LiAlH4 (1.11 g, 30 mmol) in ether (100 ml) stirred under N2 at 25°. Powerful gas evolution and weak exothermic! After 3 hours, the reaction mixture was carefully cooled and water (1 ml), aqueous sodium hydroxide solution (10% w/v,

1 ml) and water (3 ml). Powerful gas development and exothermic! The mixture was vacuum filtered and the residue washed with ether

(100ml). The combined filtrates were extracted with dilute hydrochloric acid (0.1M, 2 x 100 ml). The aqueous layer was washed with ether (2 x 50 mL), basified with NaOH pellets (1.0 g, 25 mmol) and extracted with ether (3 x 25 mL). The combined extracts were washed with water (2 x 25 ml, (often emulsions)), saturated brine (25 ml) and dried (MgSO 4 ). The solvent was removed under reduced pressure to afford the desired amine (1.00 g, 45%) as a pale yellow oil.

NMR (CDCl 3 ) δ 7.1-7.3 (5H, m); 6.9-7.1 (3H, m); 4.56 (1H, double doublet, J=6.8Hz); 3.61-3.35 (2H, ABq of ds, JAB=12.5Hz, Jd=6.8Hz); 2.18 (6H, s); 1.16 (2H, br s).

c) N,6-(2,6-dimethylphenyl)-2-phenethyl)adenosine

6-chloropurine riboside (1.28 g, 4.4 mmol), 2-(2,6-dimethylphenyl)-2-phenylethylamine (1.00 g, 4.4 mmol) and triethylamine (0.89 g, 8 .8 mmol), was refluxed in ethanol (40 mL) under N 2 and stirring for 15 h. The solvent was removed under reduced pressure to give a faint brown

solid foam which was added to ethyl acetate (50 mL), washed with water (2 x 25 mL, emulsion!), saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the remaining solid foam purified by chromatography on silica gel eluting with 5% CH 3 OH in CHCl 3 . The solvent was removed under reduced pressure to give the desired nucleoside (1.44 g, 67%) as a whitish solid foam, m.p. 112-124°C.

Calculated for C26H2gN504. 0 , 13 CHC13

C, 63.91; H, 5.93; N, 14.27; Cl, 2.82

Found: C, 63.42; H, 6.05; N, 14.26; Cl, 2.83

Example 2

N, 6-( 2-( 2, 6- dimethylphenyl)- 2-( 4- methylphenyl) ethyl) adenosine

2-(2,6-Dimethylphenyl)-2-(4-methylphenyl)ethylamine (0.92 g, 38%) was prepared from E,2-(2,6-dimethylphenyl)nitroethylene (1.77 g, 10 mmol, see Example 1), 4-bromotoluene (2.56 g, 15 mmol) and Mg (0.36 g, 15 mmol) followed by LiAlH 4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (1.20 g, 62%) was prepared from the amine (0.92 g, 3.8 mmol), 6-chloropurine riboside (1.11 g, 3.8 mmol) and triethylamine (0.81 g, 8 mmol) as a pale yellow solid foam, m.p. 113-122°C, as described in Example 1.

Example 3

N, 6-( 2-( 3, 5- dimethylphenyl)- 2- phenethyl) adenosine

The nitrostyrene (2.25 g, 79%) was prepared from 3,5-dimethylbenzaldehyde (2.1 g, 0.16 mol) and nitromethane (0.9 g, 0.016 mol), as described in Example 1.

The amine (0.57 g, 21%) was prepared from E,2-(3,5-dimethylphenyl)nitroethene (2.25 g, 0.012 mol), phenylmagnesium bromide (6.3 mL, 0.019 mol) followed by LiAlH 4 reduction (1.38 g, 0.036 mmol), as described in Example 1.

The nucleoside (0.62 g, 47%) was prepared from the amine (0.57 g, 0.0025 mol), 6-chloropurine riboside (0.66 g, 0.0023 mol) and triethylamine (0.3 mL, 0.0025 mol) as a solid, m.p. 94-97°C, as described in Example 1.

Example 4

N, 6-(2-naphth-1-yl-2-phenethyl)adenosine

The nitrostyrene (19.38 g, 97%) was prepared from 1-naphthaldehyde (15.62 g, 100 mmol) and nitromethane (6.1 g, 100 mmol), as described in Example 1.

The amine (3.78 g, 59%) was prepared from E,2-naphth-l-ylnitroethene (4.88 g, 25 mmol) and phenylmagnesium bromide (27 mmol) followed by LiAlH 4 reduction (2.22 g, 60 mmol ), as described in Example 1.

The nucleoside (3.43 g, 67%) was prepared from 2-naphth-1-yl-2-phenethylamine (2.56 g, 10 mmol), 6-chloropurine riboside (2.87 g, 10 mmol) and triethylamine (2.0 g, 20 mmol) as a white powder, m.p. 120-128°C, as described in Example 1.

Example 5

N, 6-( 2-( 3, 5- dichlorophenyl)- 2-( 2, 6- dimethylphenyl) ethyl) adenosine

The nitrostyrene (8.48 g, 97%) was prepared from 3,5-dichlorobenzaldehyde (7.00 g, 40 mmol) and nitromethane (2.44 g,

40 mmol), as described in Example 1.

The amine (1.39 g, 47%) was prepared from E,2-(3,5-dichlorophenyl)nitroethene (2.18 g, 10 mmol), 2,6-dimethylbromobenzene (2.78 g, 15 mmol) and Mg (0.36 g, 15 mmol) followed by LiAlH 4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (2.05 g, 77%) was prepared from 2-(3,5-dichlorophenyl)-2-(2,6-dimethylphenyl)ethylamine (1.39 g, 4.7 mmol), 6-chloropurine riboside (1.35 g, 4.7 mmol) and triethylamine (0.95 g, 9.4 mmol) as a white solid foam, m.p. 125-135°C, as described in Example 1.

Example 6

N, 6-( 2-( 2, 6- dichlorophenyl)- 2-( phenethyl) adenosine

The nitrostyrene (10.18 g, 93.4%) was prepared from 2,6-dichlorobenzaldehyde (8.75 g, 50 mmol) and nitromethane (3.05 g,

50 mmol), as described in Example 1.

/The amine (1.95 g, 45%) was prepared from E,2-(2,6-dichlorophenyl)nitroethene (3.27 g, 15 mmol) and phenylmagnesium bromide (18 mmol) followed by LiAlH4 reduction (2.22 g, 60 mmol), as described in Example 1.

The nucleoside (1.55 g, 61%) was prepared from the amine

(1.48 g, 0.0056 mol), 6-chloropurine riboside (1.40 g, 0.0049 mol) and triethylamine (1.4 mL, 0.01 mol) as a solid, m.p. 102-112°C, as described in Example 1.

Example 7

N, 6-( 2-( 3, 5- dichlorophenyl)- 2- phenethyl) adenosine

The amine (1.09 g, 41%) was prepared from E,2-(3,5-dichlorophenyl)nitroethene (2.18 g, see Example 5) and phenylmagnesium bromide (15 mmol) followed by LiAlH 4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (1.63 g, 77%) was prepared from 2-(3,5-dichlorophenyl)-2-phenethylamine (1.09 g, 4.1 mmol), 6-chloropurine riboside (1.08 g, 4 .1 mmol) and triethylamine (0.81 g, 8 mmol) as a whitish solid foam, m.p. 110-115°C, as described in Example 1.

Example 8

N, 6-( 2-( 3- chlorophenyl)- 2-( 3, 5- dichlorophenyl) ethyl) adenosine

The amine (1.08 g, 36%) was prepared from E,2-(3,5-dichlorophenyl)nitroethene (2.18 g, 10 mmol, see Example 5), 3-bromochlorobenzene (3.83 g, 20 mmol ) and Mg (0.36 g, 15 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (1.53 g, 77%) was prepared from 2-(3-chlorophenyl)-2-(3,5-dichlorophenyl)ethylamine (1.08 g, 3.6 mmol), 6-chloropurine riboside (1 .05 g, 3.6 mmol) and triethylamine (0.71 g, 7 mmol) as a white solid foam, m.p. 107-123°C, as described in Example 1.

Example 9

N,6-(2-(3-chlorophenyl)-2-(2,6-dichlorophenyl)ethyl)adenosine

The amine (1.21 g, 40%) was prepared from E,2-(2,6-dichlorophenyl)nitroethene (2.18 g, 10 mmol, see Example 6), 3-bromochlorobenzene (3.83 g, 20 mmol ) and Mg (0.36 g, 15 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (0.84 g, 38%) was prepared from 2-(3-chlorophenyl)-2-(2,6-dichlorophenyl)ethylamine (1.21 g, 4 mmol), 6-chloropurine riboside (1.15 g, 4 mmol) and triethylamine (0.81 g, 8 mmol) as a pale yellow solid foam, m.p. 113-125°C, as described in Example 1.

Example 10

N, 6-( 2-( 3- chlorophenyl)- 2-( 3, 5- dimethoxyphenyl) ethyl) adenosine

The nitrostyrene (14.41 g, 97%) was prepared from 3,5-dimethoxybenzaldehyde (12.2 g, 73 mmol) and nitromethane (4.6 g,

75 mmol), as described in Example 1.

The amine (0.46 g, 26%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (1.25 g, 0.006 mol), 3-bromochlorobenzene (2.9 mL, 0.025 mol), magnesium ( 0.48 g, 0.02 mol) followed by LiAlH 4 reduction (1.40 g, 0.037 mmol), as described in Example 1.

The nucleoside (0.36 g, 44%) was prepared from the amine (0.40 g, 0.0014 mol), 6-chloropurine riboside (0.40 g, 0.0014 mol) and triethylamine (0.2 mL, 0.0015 mol) as a whitish solid, m.p. 81-86°C, as described in Example 1.

Example 11

N, 6-( 2-( 3, 5- dimethoxyphenyl)- 2- phenethyl) adenosine

The amine (10.4 g, 59%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (14.41 g, 68 mmol, see Example 10) and phenylmagnesium bromide (100 mmol) followed by LiAlH 4 reduction ( 7.77 g, 210 mmol), as described in Example 1.

The nucleoside (17.14 g, 83%) was prepared from the amine (10.4 g, 40 mmol), 6-chloropurine riboside (11.5 g, 0.40 mmol) and triethylamine (8.08 g, 80 mmol) ) as a whitish solid foam, m.p. 97-105°C, as described in Example 1.

Example 12

N, 6-( 2-( 2, 5- dimethoxyphenyl)- 2- phenethyl) adenosine

The nitrostyrene (7.65 g, 49%) was prepared from 2,5-dimethoxybenzaldehyde (12.5 g, 0.075 mol) and nitromethane (4.58 g, 0.075 mol), as described in Example 1.

The amine (1.04 g, 21%) was prepared from E,2-(2,5-dimethoxyphenyl)nitroethene (7.0 g, 0.033 mol), phenylmagnesium bromide (15.8 mL, 0.047 mol) followed by LiAlH 4 reduction (2.90 g, 0.076 mol), as described in Example 1.

The nucleoside (0.43 g, 23%) was prepared from the amine (1.04 g, 0.004 mol), 6-chloropurine riboside (1.03 g, 0.0036 mol) and triethylamine (0.5 mL, 0.004 mol ) as a solid, m.p. 96-100°C, as described in Example 1.

Example 13

N, 6-( 2^( 2, 6- dimethoxyphenyl)- 2- phenethyl) adenosine

The nitrostyrene (6.87 g, 82%) was prepared from 2,6-dimethoxybenzaldehyde (6.5 g, 37 mmol) and nitromethane (2.29 g,

37 mmol), as described in Example 1.

The amine (0.49 g) was prepared in highly impure form from E,2-(2,6-dimethoxyphenyl)nitroethene (2.09 g, 10 mmol) and phenyllithium (15 mmol in ether/cyclohexane) followed by LiAlH 4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (0.29 g, 6% based on nitrostyrene) was prepared from crude 2-(2,6-dimethoxyphenyl)-2-phenethylamine (0.49 g), 6-chloropurine riboside (0.58 g, 2 mmol ) and triethylamine (0.40 g, 4 mmol), as described in Example 1, with the exception of a further purification on silica gel plates for preparative chromatography, in which two elutions were carried out with 8% CH3OH in CHCl3, as a yellow-brown solid foam, m.p. . 112-121°C.

Example 14

N, 6-( 2-( 2- methoxyphenyl)- 2-( 3- methoxyphenyl) ethyl) adenosine

The nitrostyrene (32.5 g, 91%) was prepared from 2-methoxybenzaldehyde (27.2 g, 0.2 mol) and nitromethane (12.2 g, 0.2 mol), as described in Example 1.

The amine (1.81 g, 28%) was prepared from E,2-(2-methoxyphenyl)nitroethene (4.48 g, 0.025 mol), 3-methoxybromobenzene (6.3 mL, 0.05 mol), magnesium ( 0.97 g, 0.04 mol) followed by LiAlH 4 reduction (2.43 g, 0.064 mmol), as described in Example 1.

The nucleoside (1.20 g, 37%) was prepared from the amine (1.80 g, 0.007 mol), 6-chloropurine riboside (1.72 g, 0.006 mol) and triethylamine (0.9 mL, 0.0066 mol ) as a beige colored foam, m.p. 103-105°C, as described in Example 1.

Example 15

N, 6-( 2-( 3, 4- dimethoxyphenyl)- 2- phenethyl) adenosine

The nitrostyrene (12.23 g, 39%) was prepared from 3,4-dimethoxybenzaldehyde (24.9 g, 0.15 mol) and nitromethane (9.15 g, 0.15 mol), as described in Example 1.

The amine (1.18 g, 12%) was prepared from E,2-(3,4-dimethoxyphenyl)nitroethene (8.82 g, 0.042 mol), phenylmagnesium bromide (20.7 mL, 0.06 mol) followed by LiAlH4 -reduction (2.55 g,

0.067 mmol), as described in Example 1.

The nucleoside (1.24 g, 59%) was prepared from the amine

(1.16 g, 0.0045 mol), 6-chloropurine riboside (1.09 g, 0.0038 mol) and triethylamine (0.6 mL, 0.0042 mol) as a solid, m.p. 96-104°C, as described in Example 1.

Example 16

N, 6-( 2-( 3, 5- diethoxyphenyl)- 2- phenethyl) adenosine

The nitrostyrene (2.73 g, 88%) was prepared from 3,5-diethoxybenzaldehyde (2.68 g, 0.014 mol) and nitromethane (0.86 g, 0.014 mol), as described in Example 1.

The amine (1.25 g, 37%) was prepared from E,2-(3,5-diethoxy-phenyl)nitroethene (2.73 g, 0.012 mol), phenylmagnesium bromide (6.3 mL, 0.019 mol) followed by LiAlH4 -reduction (1.17 g, 0.031 mol), as described in Example 1.

The nucleoside (1.62 g, 74%) was prepared from the amine

(1.23 g, 0.004 mol), 6-chloropurine riboside (1.15 g, 0.004 mol), and triethylamine (0.6 mL, 0.0044 mol) as a white foam, m.p. 88-93°C, as described in Example 1.

Example 17

N, 6-( 2-( 3, 5- dimethoxyphenyl)- 2- thien- 2- ylethyl) adenosine

The amine (1.60 g, 27%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (5.23 g, 0.025 mol, see Example 10), 2-bromothiophene (5.2 mL, 0, 05 mol) and magnesium (0.96 g, 0.04 mol) followed by LiAlH 4 reduction (3.80 g, 0.10 mmol), as described in Example 1.

The nucleoside (1.61 g, 59%) was prepared from the amine

(1.38 g, 0.0052 mol), 6-chloropurine riboside (1.35 g, 0.0047 mol)

and triethylamine (0.7 mL, 0.0052 mol) as a solid, m.p. 80-83°C, as described in Example 1.

Example 18

N, 6-( 2-( 3, 5- dimethoxyphenyl)- 2- naphth- 1- ylethyl) adenosine

The amine (0.48 g, 14%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (2.22 g, 0.011 mol, see Example 10), 1-bromonaphthalene (3.1 mL, 0.022 mol) and magnesium (0.43 g, 0.018 mol) followed by LiAlH 4 reduction (0.90 g, 0.024 mol), as described in Example 1.

The nucleoside (0.22 g, 25%) was prepared from the amine

(0.48 g, 0.0016 mol), 6-chloropurine riboside (0.40 g, 0.0014 mol) and triethylamine (0.2 mL, 0.0015 mol) as a solid, m.p. 114-118.5°C, as described in Example 1.

Example 19

N, 6-( 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl) ethyl) adenosine

The amine (1.90 g, 67%) was prepared from E,2-(3,5-dimethoxy)nitroethylene (2.09 g, 10 mmol, see Example 10), 2-bromotoluene (2.57 g, 15 mmol ) and magnesium (0.36 g, 15 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (2.85 g, 79%) was prepared from 2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (1.90 g, 6.7 mmol), 6-chloropurine riboside (1 .94 g, 6.7 mmol) and triethylamine (1.31 g,

13 mmol) as a whitish solid foam, m.p. 105-112°C, as described in Example 1. Example 20 N, 6-( 2-( 3, 5- dimethoxyphenyl)- 2-( 2, 6- dimethylphenyl) ethyl) adenosine Amine (2.05 g, 71% ) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (2.09 g, 10 mmol, see Example 10), 2,6-dimethylbromobenzene (2.78 g, 15 mmol) and magnesium (0.36 g, 15 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (2.23 g, 79%) was prepared from 2-(3,5-dimethoxyphenyl)-2-(2,6-dimethylphenyl)ethylamine (2.05 g, 7 mmol), 6-chloropurine riboside (2 .05 g, 7 mmol) and triethylamine (1.41 g, 14 mmol) as a white solid foam, m.p. 107-117°C, as described in Example 1.

Example 21

N, 6-( 2-( 3, 5- dimethoxyphenyl)- 2-( 3- methoxyphenyl) ethyl) adenosine

The amine (1.70 g, 59%) was prepared from E,2-(3,5-dimethoxyphenyl) nitroethene (2.09 g, 10 mmol, see Example 10), 3-bromoanisole (2.80 g, 15 mmol ) and magnesium (0.48 g, 20 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (2.42 g, 76%) was prepared from 2-(3,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethylamine (1.70 g, 6 mmol), 6-chloropurine riboside (1.72 g, 6 mmol) and triethylamine (1.21 g, 12 mmol) as a beige solid foam, m.p. 90-101°C, as described in Example 1.

Example 22

N, 6-( 2-( 3, 4, 5- trimethoxyphenyl)- 2- phenethyl) adenosine

The nitrostyrene (31.21 g, 63%) was prepared from 3,4,5-trimethoxybenzaldehyde (40.8 g, 0.21 mol) and nitromethane (12.4 g, 0.20 mol), as described in Example 1 .

The amine (0.84 g, 4%) was prepared from E,2-(3,4,5-trimethoxyphenyl)nitroethene (15.72 g, 0.066 mol), phenylmagnesium bromide (29.6 mL, 0.089 mol) followed by LiAlH4 -reduction (1.83 g, 0.048 mol), as described in Example 1.

The nucleoside (1.25 g, 85%) was prepared from the amine

(0.82 g, 0.0029 mol), 6-chloropurine riboside (0.75 g, 0.0026 mol) and triethylamine (0.4 mL, 0.0029 mol) as a solid, m.p. 95-99°C, as described in Example 1.

Example 23

N, 6-( 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methoxyphenyl) ethyl) adenosine

The amine (5.26 g, 46%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (8.36 g, 0.04 mol, see Example 10), 2-methoxybromobenzene (10.2 mL, 0.08 mol) and magnesium (1.57 g, 0.064 mol) followed by LiAlH 4 reduction (5.98 g, 0.16 mol), as described in Example 1.

The nucleoside (5.15 g, 90%) was prepared from the amine

(3.16 g, 0.011 mol), 6-chloropurine riboside (2.86 g, 0.01 mol) and

triethylamine (1.4 mL, 0.011 mol) as a solid, m.p. 93-97°C, as described in Example 1.

Example 24

N, 6-( 2-( 3, 4, 5- trimethoxyphenyl)- 2-( methylphenyl) ethyl) adenosine

The amine (1.01 g, 31%) was prepared from E,2-(3,4,5-trimethoxyphenyl)nitroethene (2.39 g, 10 mmol, see Example 22), 2-bromotoluene (2.57 g, 15 mmol) and magnesium (0.36 g, 15 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (1.16 g, 66%) was prepared from 2-(3,4,5-trimethoxyphenyl)-2-(2-methylphenylethylamine (1.01 g, 3 mmol), 6-chloropurine riboside (0.89 g, 3 mmol) and triethylamine (0.61 g, 6 mmol) as a white solid foam, mp 107-115°C, as described in Example 1.

Example 25

N, 6-( 2-( 2- methoxyphenyl)- 2-( 3, 4, 5- trimethoxyphenyl) ethyl) adenosine

The amine (0.70 g, 9%) was prepared from E,2-(3,4,5-trimethoxyphenyl)nitroethene (5.98 g, 0.025 mmol, see Example 22), 2-methoxybromobenzene (6.4 mL, 0.05 mol) and magnesium (0.97 g, 0.04 mol) followed by LiAlH 4 reduction (2.43 g, 0.064 mol), as described in Example 1.

The nucleoside (0.67 g, 54%) was prepared from the amine

(0.70 g, 0.0022 mol), 6-chloropurine riboside (0.57 g, 0.002 mol)

and triethylamine (0.3 mL, 0.0022 mol) as a gray foam, m.p. 99-104°C, as described in Example 1.

Example 26

N, 6-( 2-( 2- methoxyphenyl)- 2-( 3-( trifluoromethyl) phenyl) ethyl) adenosine

The nitrostyrene (9.84 g, 91%) was prepared from 3-(trifluoromethyl)benzaldehyde (8.7 g, 50 mmol) and nitromethane (3.1 g,

50 mmol), as described in Example 1.

The amine (1.72 g, 57%) was prepared from E,2-(3-trifluoromethyl)phenyl)nitroethylene (2.17 g, 10 mmol), 2-bromoanisole (2.81 g, 15 mmol) and magnesium (0.36 g, 15 mmol), as described in Example 1.

The nucleoside (2.22 g, 71%) was prepared from 2-(2-methoxyphenyl)-2-(3-(trifluoromethyl)phenyl)ethylamine (1.72 g,

5.7 mmol), 6-chloropurine riboside (1.78 g, 6.2 mmol) and triethylamine (1.2 g, 12 mmol) as a pale yellow solid foam, m.p. 100-108°C, as described in Example 1.

Example 27

N, 6-( 2-( 2- methoxyphenyl)- 2-( 3, 5- bis( trifluoromethyl) phenyl) ethyl) adenosine

The nitrostyrene (5.48 g, 87%) was prepared from 3,5-bis-(trifluoromethyl)benzaldehyde (5.77 g, 22 mmol) and nitromethane (2.69 g, 44 mmol), as described in Example 1.

The amine (0.76 g, 42%) was prepared from E,2-(3,5-bis-(trifluoromethyl)phenyl)nitroethene (1.43 g, 5 mmol), 2-bromoanisole (1.39 g, 7 .5 mmol) and magnesium (0.18 g, 7.5 mmol) followed by LiAlH4 reduction (0.55 g, 15 mmol), as described in Example 1.

The nucleoside (0.97 g, 75%) was prepared from 2-(2-methoxyphenyl)-2-(3,5-bis(trifluoromethyl)phenyl)ethylamine (0.76 g, 2.1 mmol), 6-chloropurine -riboside (0.61 g, 2.1 mmol) and triethylamine (0.40 g, 4 mmol) as a white solid foam, m.p. 105-112°C, as described in Example 1.

Example 28

N, 6-( 2-( 3, 5- bis( trifluoromethyl) phenyl- 2- phenethyl) adenosine

The amine (0.92 g, 27%) was prepared from E,2-(3,5-bis-(trifluoromethyl)phenyl)nitroethene (2.85 g, 10 mmol, see Example 27) and phenylmagnesium bromide (15 mmol) followed by of LiAlH4 reduction (1.11 g, 30 mmol), as described in Example 1.

The nucleoside (1.20 g, 75%) was prepared from 2-(3,5-bis(trifluoromethyl)phenyl)-2-phenethylamine (0.92 g, 2.7 mmol), 6-chloropurine riboside (0, 80 g, 2.7 mmol) and triethylamine (0.60 g,

6 mmol) as a pale yellow solid foam, m.p. 99-105°C, as

.described in Example 1.

Example 29

N6_((_)- 2-( 3 t 5- dimethoxyphenyl)- 2-( 2- methylphenyl) ethyl) adenosine

(±)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (40.65 g, 0.15 mol) and [2R,3R]dibenzoyltartaric acid monohydrate

(56.4 g, 0.15 mol) was dissolved in EtOH under reflux (ca. 700 mL) and then recrystallized 5 times while seeding with crystals of optically enriched salt (prepared in 94% EE by recrystallization of a small sample 10 times ) to form 5.78 g of salt, EE = 93.4%, m.p. 175.5-177°C,

[a]g<3>(MeOH) -93.5°. The ammonium salt (5.00 g) was partitioned between dilute NaOH solution (1N, 30 mL) and ether (50 mL). The layers were separated and the aqueous layer extracted with more ether (25 mL). The combined organic phases were washed with water (2 x 25 mL), saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure to give (-)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (2.08 g) as a cloudy pale yellow oil [a]g<3 >(MeOH) -57.4°, EE = 93.4%.

The nucleoside (3.53 g, 90%) was prepared from (-)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (2.02 g, 7.45 mmol), 6-chloropurine -riboside (2.16 g, 7.5 mmol) and NEt 3 (1.51 g, 15 mmol) in ethanol (70 mL) at reflux with stirring under N 2 for 18 h. On cooling, the desired nucleoside crystallized out (3.53 g, 90%) as white microscopic needles, m.p. 195-197°C, Rotation [a]g<3>(DMSO) -78.1°. Diastereoisomeric excess 90%.

Example 30

N6-((+)- 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl) ethyl) adenosine

The mother liquor from the first crystallization of (±)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylammonium-di-o-benzoyl-[2R,3R]tartrate, described in Example 29, was evaporated to dryness. Stirring was then carried out with dilute NaOH solution (0.4M, 500 ml) and ether (100 ml) until all solids had dissolved. The layers were separated and the aqueous layer extracted with more ether (2 x 100 mL). The combined ether extracts were washed with NaOH solution (0.25M, 100 mL), water (100 mL), saturated brine (100 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure to give 2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (17.2 g) 2:1 enriched with respect to the (+)-enantiomer. This was mixed with D-dibenzoyl tartrate.H 2 O (23.88 g, 63.5 mmol) and recrystallized 3 times from ethanol, seeding with crystals of optically enriched salt to give 6.60 g of salt. EE = 91%, m.p. 169-171°C, [α]g<3>(MeOH) +96°.

The salt (5.00 g) was partitioned between NaOH solution (1M, 30 mL) and ether (50 mL). The layers were separated and the ether layer extracted with more ether (25 mL). The combined organic phases were washed with water (2 x 25 mL), saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure to give (+)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (2.09 g)

as a cloudy pale yellow oil. [a]g<3>(MeOH) +53.3°. EE = 87%

(estimated).

The nucleoside was prepared from (+)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (2.03 g, 7.5 mmol), 6-chloropurine riboside (2.16 g, 7 .5 mmol) and NEt3 (1.51 g, 15 mmol) in ethanol under reflux and stirring under N2 for 18 h. The solvent was removed under reduced pressure, the residue added to water (50 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic phases were washed with water (25 mL), saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the residue recrystallized from EtOH (25 mL) at 0°C to give N<6->((+)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl )adenosine (2.86 g, 74%) as white needles, m.p. 168-169°C. Rotation [a]g<3>(DMSO) -5.5°. Diastereoisomeric excess 80%.

Example 31

5'- bromo- 5'- deoxy- N6-( 2, 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl) ethyl) adenosine

A solution of 5'-bromo-5<1->deoxy-S-phenylthioinosine-S,S-dioxide-2',3'-di-o-isopropylidene (3.0 g, 6 mmol), 2-(3 ,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (1.83 g, 6 mmol) and NEt 3 (1.21 g, 12 mmol) were stirred in CHCl 3 (30 mL) under N 2 at 25 °C for 40 h . The mixture was poured into a NaH 2 PO 4 solution (0.4 M, 50 mL). The layers were separated and the aqueous layer extracted with more CHCl 3 (30 mL). The organic extracts were washed with water (2 x 30 mL), saturated brine (30 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the remaining solid foam added to 10% aqueous TFA (10 mL) and stirred under N 2 at 0°C for 45 min. The reaction mixture was poured into Na 2 CO 3 solution (1M, 200 mL) and extracted with EtOAc (3 x 50 mL). The combined extracts were washed with water (2 x 25 ml), saturated brine (25 ml) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel (225 g), eluting with 5% MeOH in CHCl 3 to give 5'-bromo-5'-deoxy-N<6->(2- (3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine (2.07 g, 56%) as a pale yellow solid foam, m.p. 76-91°C.

Example 32

N6-( 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl) ethyl) adenosine-5'-uronic acid

6-chloropurine riboside-2<1>,3'-di-o-isopropylidene

Triethyl orthoformate (59.2 g, 0.4 mol) was added to a suspension of 6-chloropurine riboside (28.75 g, 0.10 mol) and tosic acid monohydrate (18 g, 0.095 mol) in acetone ( 1 liter) and stirred under N2 at 25°. After 3 hours, the thus clear solution was concentrated under reduced pressure and the residue poured into K 2 HPO 4 solution (26.1 g, in 800 ml) and extracted with ethyl acetate (2 x 200 ml). The combined extracts were washed with water (2 x 100 mL), saturated brine (100 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure to give 6-chloropurine riboside-2',3'-di-o-isopropylidene (28.5 g, 87%) as a pale yellow crystalline solid, m.p. 155-158°C.

6-chloropurine riboside-2',3'-di-o-isopropylidene-5'-uronic acid

A solution of chromic acid (2M) in aqueous sulfuric acid (3M, 100 ml) was added over 1 hour to partially dissolved 6-chloropurine riboside-2',3'-di-o-isopropylidene (32.65 g, 100 mmol) in acetone (500 ml) and stirred under N2 at 25° without cooling. After an additional 15 minutes, the mixture was filtered with Celite and the residue washed with EtOAc (2 x 250 mL). The combined filtrates were washed with Na 2 S 2 O 5 solution (0.5 M, 50 mL) and water (3 x 50 mL). The organic phase was extracted with NaOH solution (0.5M, 250 ml). The basic extract was washed with EtOAc (200 mL) and acidified with concentrated HCl. The yellow oil was extracted with ethyl acetate (3 x 100 mL) and the organic phase washed with water (100 mL), saturated brine (100 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure to give 6-chloropurine-riboside-2',3'-di-o-isopropylidene-51-uronic acid (20.3 g, 57%) as a pale orange solid, m.p. 135-152°C. An analytical sample was recrystallized from aqueous MeOH, m.p. 180-210°C (decomp.).

N<6->(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-2<1>,3'-di-o-isopropylidene-5'-uronic acid

A solution of 6-chloropurine riboside-2',3'-di-o-isopropylidene-5'-uronic acid (3.41 g, 10 mmol), 2-(3,5-dimethoxyphenyl)-2-(methylphenyl) ethylamine (2.71 g, 10 mmol) and NEt 3

(3.03 g, 30 mmol) was refluxed in EtOH (100 mL) with stirring under N 2 i for 18 h. The solvent was removed under reduced pressure and the residue dissolved in NaOH solution (0.25M, 50 mL), washed with EtOAc (2 x 25 mL), acidified with concentrated HCl and then extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (2 x 25 mL), saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure to give N<6->

(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-2',3<1->di-o-isopropylidene-5'-uronic acid (4.94 g, 82%) as a pale yellow solid foam, m.p. 113-121°C.

N<6->(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-5'-uronic acid

N<6->(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-2',3<1->di-o-isopropylidene-5'-uronic acid (1.50 g , 2.6 mmol) was stirred in aqueous TFA (10 mL, 1:9) under N 2 at 0 °C for 4 h. The reaction mixture was cooled by pouring into EtOAc

(50 mL), after which most of the TFA was washed out with NaOH solution (2.2M, 50 mL) and NaH 2 PO 4 solution (0.2 M, 50 mL). The organic phase was washed with saturated brine (50 mL), dried (MgSO 4 ), whereupon the solution was concentrated under reduced pressure before

remaining volatiles were removed azeotropically with toluene three times. The remaining solid foam was dissolved in EtOH (24 mL) and triturated with ether to give N<6->(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-5'-uronic acid (0 .71 g, 51%) as a white powder, m.p. 129-139°C.

Example 3 3

N6-( 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl) ethyl) adenosine- 5'-uronamide

Dicyclohexylcarbodiimide (0.55 g, 2.7 mmol) was added to a suspension of 1-hydroxybenzotriazole (0.32 g, 2.4 mmol)

in CH2Cl2 (20 mL) containing N<6->(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-2',3'-di-o-isopropylidene-5<1- >uronic acid (Example 32, 1.15 g, 2 mmol) and stirred under N2 at 0°. After 10 minutes, NH 3 was bubbled through the mixture for 15 minutes at 0°C, after which the mixture was allowed to warm to 25°C. It was then vacuum filtered, after which the residue was washed with CH 2 Cl 2 (10 mL)

and the solvent removed from the combined filtrates under reduced pressure. The remaining glassy solid was dissolved in aqueous TFA (10 mL, 1:9) and stirred under N 2 at 0°C for 2.5 h. The reaction mixture was poured into NaOH solution (125 mL, 1M) and extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL), saturated brine (50 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica (150 g), eluting with 5% MeOH in CHCl 3 to give N<6->(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) )ethyl)adenosine-5'-uronamide (0.71 g, 61%) as a white crystalline solid, m.p. 181-184°C.

Example 34

N5'- methyl- N6-( 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl) ethyl)- adenosine- 5'- uronamide

Triethylamine (0.61 g, 6 mmol) and methylamine hydrochloride

(0.27 g, 4 mmol) was added in the indicated order at 1 minute intervals to a suspension of N-methyl-2-fluoro-pyridinium tosylate (0.42 g, 1.5 mmol) and N<6-> (2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-2',3'-di-o-isopropylidene-

5'-uronic acid (Example 32, 0.58 g, 1 mmol) in CH2Cl2 (5 mL)

stirred under N2 at 0°C. After 1 h, the reaction mixture was diluted with EtOAc (25 mL) and washed with dilute HCl (1M, 10 mL), water (10 mL), saturated brine (10 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the remaining solid foam dissolved in aqueous TFA (5 mL, 1:9 at 0°C) stirred under N 2 in 2 h. The reaction mixture was cooled by addition of EtOAc (50 mL) and washed with NaOH solution (1M, 50 mL), dilute Na 2 CO 3 solution (50 mL) and saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the residue purified by preparative TLC (silica), eluting with 10% MeOH in CHCl3 to give N5'-methyl-N<6->(2-(3,5-dimethoxyphenyl)-2-( 2-Methylphenyl)ethyl)adenosine-5'-uronamide (0.36 g, 64%) as a white glassy foam, m.p. 122-127°C.

Example 35

N5' ethyl- N6-( 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl) ethyl)- adenosine- 5'- uronamide

Dicyclohexylcarbodiimide (0.52 g, 2.5 mmol) was added

to a suspension of 1-hydroxybenzotriazole (0.27 g, 2 mmol) in CH 2 Cl 2 (20 mL) containing N<6->(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine- 2',3'-di-o-isopropylidene-5'-uronic acid (Example 32, 1.15 g, 2 mmol) stirred under N 2 at 0°C. After 10 minutes, ethylamine (0.27 mL, 4 mmol) was added. After 16 h, the reaction mixture was filtered and the residue washed with CH 2 Cl 2 (10 mL). The solvent was removed from the combined filtrates under reduced pressure and the remaining pale yellow solid foam dissolved in aqueous TFA (10 mL, 1:9) at 0°C and stirred under N 2 for 75 min. The reaction mixture was cooled with EtOAc (100 mL) and washed with NaOH solution (1M, 100 mL),

saturated Na 2 CO 3 solution (50 mL), saturated brine (50 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel (100 g) eluting with 5% MeOH in CHCl 3 to give N<5>'-ethyl-N<6->(2-(3,5-dimethoxyphenyl) -2-(2-methylphenyl)ethyl)adenosine-5'-uronamide (0.86 g, 72%) contaminated with ca. 10 mole percent

dicyclohexylurea, as a pale yellow solid foam, m.p. 103-112°C.

Example 36

N5'- cyclopropyl- N6-( 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl) ethyl)- adenosine- 5'- uronamide

Triethylamine (0.20 g, 2 mmol) and cyclopropylamine (0.11 g,

2 mmol) were added in the indicated order at 2 minute intervals to a mixture of N-methyl-2-fluoropyridinium tosylate (0.42 g, 1.5 mmol) and N<6->(2-(3,5-dimethoxyphenyl )-2-(2-methylphenyl)ethyl)adenosine-2',3'-di-o-isopropylidene-5'-uronic acid (Example 32, 0.58 g, 1.0 mmol) and stirred in CH 2 Cl 2 (5 mL ) under N2 at 25°C. After 15 min, the reaction mixture was diluted with EtOAc (25 mL) and washed with dilute HCl (0.5 M, 10 mL), water (10 mL), saturated brine (10 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the remaining solid foam stirred in aqueous TFA (5 mL, 1:9) under N 2 at 0 °C for 2 h. The reaction mixture was cooled with EtOAc (50 mL) and washed with NaOH solution (1M, 50 mL), dilute Na 2 CO 3 solution (50 mL), saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the residue purified by preparative TLC eluting with 10% MeOH

in CH 2 Cl 2 to give N<5>'-cyclopropyl-N<6->(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-5'-uronamide (0.39 g, 67 %) as a white glassy substance, m.p. 117-126°C.

Example 37

N5' - ethyl- N6-((-)- 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl)-ethyl) adenosine- 5'- uronamide

N-ethyl-6-chloropurine-ribofuranuronamide-2<1>,3'-di-o-isopropylidene

Triethylamine (1.01 g, 10 mmol) was added to a suspension of 6-chloropurine-ribofuranuronic acid-2<1>,3'-di-o-isopropylidene (1.70 g, prepared in Example 32) and N-methyl -2-fluoropyridinium tosylate (2.12 g, 7.5 mmol) and stirred in CH 2 Cl 2 (25 mL) under N 2 at 0 °C. After 15 minutes, triethylamine (1 ml approx. 15 mmol) was added. After an additional 1 hour, the reaction mixture was poured onto dilute HCl (1N, 25 mL), the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (25 mL). The combined organic phases were washed with water (25 mL), saturated brine (25 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel eluting with hexane/EtOAc to give N-ethyl-6-chloropurine-ribofuran-uronamide-2',3'-di-o-isopropylidene (1.20 g , 65%) as a whitish solid foam, m.p. 73-80°C.

N5' - ethyl- N6-((-)- 2-( 3, 5- dimethoxyphenyl)- 2-( 2- methylphenyl)-ethyl) adenosine- 5'- uronamide

(-)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine

(0.17 g, 0.6 mmol, prepared as in Example 29), N-ethyl-6-chloropurine-ribofuranuronamide-2',3'-di-o-isopropylidene (0.22 g, 0.6 mmol) and triethylamine (0.12 g, 1.2 mmol) was refluxed in EtOH (6 mL) under N 2 for 20 h. The volatiles were removed under reduced pressure and the remaining glassy material was stirred in aqueous TFA (1:9, 5 mL) under N 2 at 0°C for 2 h. The mixture was diluted with EtOAc (50 mL)

and washed with dilute NaOH (1M, 50 mL), dilute Na 2 CO 3 solution (50 mL), saturated brine (50 mL) and dried (MgSO 4 ). The solvent was removed under reduced pressure and the residue was purified by preparative TLC (10% MeOH in CHCl 3 , rf 0.28) to give N5'-ethyl-N6-((-)-2-(3,5-dimethoxyphenyl) -2-(2-methylphenyl)ethyl)adenosine-5-uronamide (0.28 g, 83%) as a white glassy substance, m.p. 110-120°C.

Claims (15)

1. Connection by formula or a pharmaceutically acceptable acid addition salt thereof, wherein Ar is or where A is oxygen or sulfur and Xlt Xz , X3 , Ylf Y2 and Y3 may independently be selected from hydrogen, halogen, lower alkyl, lower alkylthio or alkoxy, and where X1; X2 and X3 can further be trifluoromethyl, under the condition that Y2 or Y3 must be hydrogen and Y2 and Y3 together are -(CH)4 -, under the further general condition that at least two of X1 # X2 , X3 , Yl f Y2 and Y3 is not hydrogen, R 2 ' and R 3 ' are each independently hydrogen, alkanoyl of 2-12 carbon atoms in a straight or branched alkyl chain, which may be substituted with amino, benzoyl or benzoyl substituted with lower alkyl, lower alkoxy, halogen or trifluoromethyl, wherein R 2 ' and R 3 ' can further be linked together to give either a 5-membered alkylidene ring with up to a total of 20 carbon atoms, which e.g. isopropylidene, or a cyclic phosphate diester, and R 5 ' may be phosphate, hydrogen or dihydrogen phosphate, or an alkali metal or ammonium or dialkali or diammonium salt thereof, Z is -(CH2 )-Q, where Q is selected from hydrogen, hydroxy, halogen, cyano, azido, amino, lower alkoxy, lower acyloxy, lower thioalkyl, lower sulfonylalkyl, -P(=Y)(OR")2 , -P(=Y)(OR")(OR'" ), and together with R <3> forms where Y is oxygen or sulfur and R" and R"' are independently hydrogen or lower alkyl, or (2) where J is 0, S, NR7 , where R7 is hydrogen, lower alkyl or cycloalkyl with from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and the like, or 1- or 2-methyl-cyclopropyl, 1- or 2- ethylcyclobutyl and the like, and T is (a) NR4 R5 , where R4 is straight-chain lower alkyl of 1-4 carbon atoms, hydroxy-, lower alkoxy- or halogen-substituted straight-chain lower alkyl of 1-4 carbon atoms, cyclopropyl, secondary alkyl of 3-6 carbon atoms, hydroxy-, lower alkoxy- or halogen-substituted secondary alkyl with 3-6 carbon atoms, alkenyl with 3-6 carbon atoms, aralkyl with 1-4 carbon atoms in the alkyl chain and optionally substituted in the aryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups, and hetero-arylalkyl with 1-4 carbon atoms in the alkyl chain and optionally substituted in the heteroaryl ring with hydroxy, halogen, lower alkoxy or lower alkyl groups, and R5 is hydrogen or straight-chain lower alkyl with 1-4 carbon atoms, or (b) 0R4 , where R4 has the above meaning. 2. Connection according to claim 1, characterized by atZer -(CH2 )-Q, where Q is OH. 3. Connection according to claim 2, characterized in that R2' and R3' are OH, and Ar is where Z has the above meaning, Y is Yx as defined above, when Y1 is not hydrogen. 4. Connection according to claim 2, characterized by X1( X2 , where Ar is where Y has the meaning given above, and Z is -C(0)N(H)C2 H4 . 5. Connection according to claim 1, characterized in that it is N,6-(2-(2,6-dimethylphenyl)-2-phenethyl)adenosine, N,6-(2-(2,6-dimethylphenyl)-2-(4-methylphenyl)ethyl) adenosine, N,6-(2-(3,5-dimethylphenyl)-2-phenethyl)adenosine, N,6-(2-naphth-1-yl-2-phenethyl)adenosine, N,6-(2-(3,5-dichlorophenyl)-2-(2,6-dimethylphenyl)ethyl)adenosine, N,6-(2-(2,6-dichlorophenyl)-2-(phenethyl) adenosine, N,6-(2-(3,5-dichlorophenyl)-2-phenethyl)adenosine, N,6-(2-(3-chlorophenyl)-2-(3,5-dichlorophenyl)ethyl)adenosine, N ,6-(2-(3-chlorophenyl)-2-(2,6-dichlorophenyl)ethyl)adenosine, N,6-(2-(3-chlorophenyl)-2-(3,5-dimethoxyphenyl)ethyl)adenosine , N,6-(2-(3,5-dimethoxyphenyl)-2-phenethyl)adenosine, N,6-(2-(2,5-dimethoxyphenyl)-2-phenethyl)adenosine, N,6-(2- (2,6-dimethoxyphenyl)-2-phenethyl)adenosine, N,6-(2-(2-methoxyphenyl)-2-(3-methoxyphenyl)ethyl)adenosine, N,6-(2-(3,4- dimethoxyphenyl)-2-phenethyl)adenosine, N, 6-(2-(3,5-diethoxyphenyl)-2-phenethyl)adenosine, N,6-(2-(3,5-dimethoxyphenyl)-2-thien-2 -yl)ethyl)adenosine, N,6-(2-(3,5-dimethoxyphenyl)-2-naphth-1-ylethyl)adenosine, N,6-(2-(3,5-dimethoxyphenyl)-2-( 2-methylphenyl)ethyl)adenosine, N,6-(2-(3,5-dimethoxyphenyl)-2-(2,6-dimethylphenyl)ethyl)adenosine, N,6-(2-(3,5-dimethoxyphenyl) -2-(3-methoxyphenyl)ethyl)adenosine, N,6-(2-(3,4,5-trimethoxyphenyl)-2-phenethyl)adenosine, N,6-(2-(3,5-dimethoxyphenyl)- 2-(2-Methox yphenyl)ethyl)adenosine, N,6-(2-(3,4,5-trimethoxyphenyl)-2-(methylphenyl)ethyl)adenosine, N,6-(2-(2-methoxyphenyl)-2-(3, 4,5-trimethoxyphenyl)ethyl)adenosine, N,6-(2-(2-methoxyphenyl)-2-(3-trifluoromethylphenyl)ethyl)adenosine, N,6-(2-(2-methoxyphenyl)-2-( 3,5-bis(trifluoromethyl)phenyl)ethyl)-adenosine, N <6-> ((-)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine, N <6- > ((+)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine, 5'-bromo-5'-deoxy-N <6-> (2,3,5-dimethoxyphenyl )-2-(2-methylphenyl)-ethyl)adenosine, N <6-> (2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-5'-uronic acid, N <6- > (2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-5'-uronamide, N_s'-methyl-N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)-adenosine,-5'-uronamide, N <5> '-ethyl-N <6-> (2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)-adenosine-5 <1-> uronamide, N5'-cyclopropyl-N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)-adenosine-5'-uronamide, N,6-2-(3,5-bis(trifluoromethyl)phenyl)-2-phenethyl)adenosine and N5'-ethyl-N6-((-)-2-(3,5-dimethoxyphenyl)-2-(2 -methylphenyl)ethyl)-adenosine-5'-uronamide. 6. Pharmaceutical composition for the treatment of psychoses, pain, angina or congestive heart failure, characterized in that it comprises an antipsychotic, analgesic, antianginal or anticongestive heart failure effective amount of a compound according to claim 1 and a pharmacologically acceptable carrier. 7. Procedure for the treatment of psychoses in mammals suffering from this, characterized in that a compound according to claim 1 is administered to the mammals in unit dose form. 8. Method for treating pain in mammals suffering from it, characterized in that the animals are administered a compound according to claim 1 in unit dose form. 9. Method for treating angina in mammals suffering from it, characterized in that the animals are administered a compound according to claim 1 in unit dose form. 10. Method for treating congestive heart failure in mammals suffering from it, characterized in that the animals are administered a compound according to claim 1 in unit dose form. 11. Method for producing a compound according to claim 1, characterized by connecting a compound with a formula with 6-chloropurine riboside in the presence of triethylamine to obtain the compound according to claim 1. 12. Process for producing a compound according to claim 1, characterized by A) treating a compound with a formula where Xx , X2 and X3 have the meanings given above, with 1) CH3 N02 in the presence of NaOH and 2) CH3 SO2 C1 in the presence of triethylamine, B) treats the product from A) with a compound of formula where Yx , Y2 and Y3 have the meanings given above, and M is a Grignard or lithium moiety, in an aprotic solvent, then C) reduces the product from B ) by treatment with LiAlH4 , and finally D) couples the product from C ) with 6-chloropurine riboside of formula where Z has the above meaning, in the presence of triethylamine to obtain the compound according to claim 1. 13. Method for producing a compound of formula characterized by treating a compound of formula with H2 Cr04 in acetone. 14. Method for preparing the compound of formula characterized by (1) treating a compound with formula with ethyl orthoformate and tosic acid in acetone, and then (2) treating the product from step (1) with H2 Cr04 in acetone. 15. Process for producing a compound according to claim 1, where Z is where J is 0 and T is NR4 R5 , where R4 and R5 have the meanings given above, characterized by (1) reacting a compound with formula with ethyl formate and tosic acid in acetone to obtain the compound of formula (2) treating the compound of formula XI from step (1) with H 2 Cr0 4 in acetone to obtain the compound of formula then (3)(a) treats the compound of formula XII from step (2) with where Ar <1> and Ar <2> have the above meanings, in the presence of triethylamine to obtain the compound of formula and then treating the compound of formula XIII with HNR4 R5 in the presence of a coupling reagent to obtain and alternatively further treating the compound of formula XIV to obtain the compound of formula I, wherein Z is where J is 0 and T is NR 4 R 5 , where R 4 and R 5 have the meanings given above, and R 2 ' and R 3 ' are different from propylidene, or then (3)(b) treats the compound of formula XII from step (2) with HNR 4 R 5 to obtain the compound of formula and then treating the compound of formula XVI with to obtain the compound of formula and alternatively further treating the compound of formula XIV to obtain the compound of formula I, wherein Z is where J is 0 and T is NR 4 R 5 , wherein R 4 and R 5 have the above meanings and R 2 ' and R 3 ' are different from propylidene.